Submissions for variant NM_000080.4(CHRNE):c.103T>C (p.Tyr35His)

gnomAD frequency: 0.00061  dbSNP: rs144169073

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000413280	SCV000333199	uncertain significance	not provided	2015-07-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000413280	SCV000490469	likely pathogenic	not provided	2024-11-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Referred to as Y15H using alternate nomenclature; This variant is associated with the following publications: (PMID: 19544078, 21940170, 24295813, 29189923, 31980526, 17878953, 12417530, 36891870)
Athena Diagnostics	RCV000413280	SCV000612745	likely pathogenic	not provided	2016-10-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551170	SCV000641235	pathogenic	Congenital myasthenic syndrome 4A	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 35 of the CHRNE protein (p.Tyr35His). This variant is present in population databases (rs144169073, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 12417530, 17878953, 21940170, 24295813). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Tyr15His. ClinVar contains an entry for this variant (Variation ID: 282036). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CHRNE protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004609	SCV001163795	pathogenic	Congenital myasthenic syndrome 4C		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001328993	SCV001520272	pathogenic	Congenital myasthenic syndrome 4B	2019-11-26	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV002051834	SCV002318993	likely pathogenic	Tip-toe gait	2021-11-18	criteria provided, single submitter	clinical testing	Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001125182	SCV002547813	pathogenic	Congenital myasthenic syndrome	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: CHRNE c.103T>C (p.Tyr35His), also referred to as Y15H, results in a conservative amino acid change located in the neurotransmitter-gated ion-channel ligand-binding domain (IPR006202) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00064 in 251424 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CHRNE causing Congenital Myasthenic Syndrome (0.00064 vs 0.0025), allowing no conclusion about variant significance. c.103T>C has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Congenital Myasthenic Syndrome (e.g. Ealing_2002, Denning_2007, Palace_2012, Webster_2014, McMacken_2018, Clair Hou_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31980526, 17878953, 12417530, 29189923, 21940170, 24295813). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters reported the variant as pathogenic/likely pathogenic and three as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000413280	SCV003824483	likely pathogenic	not provided	2022-12-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000551170	SCV004217770	pathogenic	Congenital myasthenic syndrome 4A	2024-03-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016670	SCV005644282	likely pathogenic	Congenital myasthenic syndrome 4A; Congenital myasthenic syndrome 4C; Congenital myasthenic syndrome 4B	2024-05-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000413280	SCV005875926	likely pathogenic	not provided	2024-09-19	criteria provided, single submitter	clinical testing	The CHRNE c.103T>C; p.Tyr35His variant (rs144169073, ClinVar Variation ID: 282036), also published as Y15H, is reported in the literature in multiple individuals affected with congenital myasthenic syndrome who carried a second variant in trans (Ealing 2002, Krenn 2023, McMacken 2018, Palace 2012, Webster 2014). This variant is found in the general population with an overall allele frequency of 0.06% (180/282,748 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.897). Based on available information, this variant is considered to be likely pathogenic. References: Ealing J et al. Mutations in congenital myasthenic syndromes reveal an epsilon subunit C-terminal cysteine, C470, crucial for maturation and surface expression of adult AChR. Hum Mol Genet. 2002 Nov 15;11(24):3087-96. PMID: 12417530. Krenn M et al. The clinical and molecular landscape of congenital myasthenic syndromes in Austria: a nationwide study. J Neurol. 2023 Feb;270(2):909-916. PMID: 36308527. McMacken G et al. Congenital myasthenic syndrome with episodic apnoea: clinical, neurophysiological and genetic features in the long-term follow-up of 19 patients. J Neurol. 2018 Jan;265(1):194-203. PMID: 29189923. Palace J et al. Clinical features in a series of fast channel congenital myasthenia syndrome. Neuromuscul Disord. 2012 Feb;22(2):112-7. PMID: 21940170. Webster R et al. Fast-channel congenital myasthenic syndrome with a novel acetylcholine receptor mutation at the alpha-epsilon subunit interface. Neuromuscul Disord. 2014 Feb;24(2):143-7. PMID: 24295813.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005355587	SCV005912078	likely pathogenic	Congenital myasthenic syndrome 4A; Congenital myasthenic syndrome 4B	2023-02-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825313	SCV000966608	uncertain significance	not specified	2018-01-10	flagged submission	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr35His variant in CHRNE has been reported in the compound heterozygous state in 6 indiv iduals with congenital myasthenic syndrome, and segregated with disease in two a ffected members of one family (reported as p.Tyr15His; Ealing 2002, Palace 2012, Webster 2014). It has also been identified in 0.1% (146/126616) of European chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org; dbSNP rs144169073). In vitro functional studies provide some evidence tha t the p.Tyr35His variant may impact protein function (Ealing 2002). However, the se types of assays may not accurately represent biological function. Computation al prediction tools and conservation analysis also suggest that the variant may impact the protein, though this information is not predictive enough to determin e pathogenicity. In summary, while there is some suspicion for a pathogenic role , the clinical significance of the p.Tyr35His variant is uncertain due to its fr equency in the general population. ACMG/AMP Criteria applied: PM3_Supporting; PS 4_Moderate; PP3; PS3_Supporting; BS1_Supporting.